Journal of Pharmaceutical Sciences 106 (2017) 1453-1465

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Journal of Pharmaceutical Sciences

journal homepage: www.jpharmsci.org

Review

Gelatin and Non-Gelatin Capsule Dosage Forms

Rampurna P. Gullapalli*, Carolyn L. Mazzitelli
Dart NeuroScience LLC, 12278 Scripps Summit Drive, San Diego, California 92131

a r t i c l e i n f o a b s t r a c t

Article history: Capsules offer an alternate to tablets for oral delivery of therapeutic compounds. One advantage of
Received 29 November 2016 capsules over tablets is their amenability to deliver not only solids but also nonaqueous liquids and
Revised 2 February 2017 semisolids as a unit dose solid dosage form. Shell component is an essential part of capsule dosage forms.
Accepted 6 February 2017
Capsule shells, available as hard or soft shells, are formulated from gelatin or a non-gelatin polymeric
Available online 14 February 2017
material such as hypromellose and starch, water, and with or without a nonvolatile plasticizer. The
capsule shells may also be formulated to modify the release of their fill contents in a site-specific manner
Keywords:
capsules in the gastrointestinal tract. The goal of the current review is to provide an in-depth discussion on
gelatin polymeric film-forming materials and manufacturing technologies used in the production of capsule
hypromellose shells.
cross-linking
© 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
modified release
enteric
stability

Introduction shells, application of non-gelatin materials as gelatin substitute in

Capsule dosage forms are widely used to encapsulate powders,
granules, pellets, liquids, and semisolids (Fig. 1). Capsules can be
soft shell capsules (softgels), which are typically used to encapsu-
late nonaqueous liquid and semisolid formulations1 or hard shell
capsules, which are used to encapsulate both solid and nonaqueous
formulations.2,3 The soft capsule shells are commonly manufac-
tured from gelatin or a non-gelatin polymeric material, water,
nonvolatile plasticizer(s), and other minor additives such as opa-
cifiers and colorants. Hard capsule shells, unlike those of soft cap-
sules, do not contain a nonvolatile plasticizer. The shells of soft and
hard capsules can also be formulated either to delay the release of
their fill contents until the capsules pass through the stomach re-
gion of the gastrointestinal tract (GIT) (enteric release) or to target
the release at a specific region of the GIT (site-specific release).
Alternately, the capsule shells can also be used to contain fill
materials to provide immediate-release or modified-release
characteristics.
Gelatin has been used predominantly as the film former for both
hard shell and soft shell capsules. In recent years, several non-
gelatin polymers have been advanced either to replace gelatin
partially or all together in the manufacture of capsule shells or to
modify the properties of capsule shells. In this article, we review
chemistry and properties of gelatin briefly as pertinent to capsule
* Correspondence to: Rampurna P. Gullapalli (Telephone: 914-316-4935; Fax: 858-
736-3056).
E-mail address: RampurnaL@gmail.com (R.P. Gullapalli).
capsule shells, and approaches to modify the properties of capsule
shells to control the release of their encapsulated fill contents.
Gelatin Capsule Dosage Forms
Composition of Gelatin Capsule Shells
Gelatin
Gelatin is a purified protein obtained from collagen of animals
(including fish and poultry) by partial alkaline and acid hydrolysis,
by enzymatic hydrolysis, or by thermal hydrolysis (United States
Pharmacopeia and National Formulary). Gelatin is a mixture of
water-soluble proteins and water (8%-15%). The protein fraction
contains almost entirely of amino acids in L-configuration with
traces in D-configuration linked by amide (peptide) bonds forming
a linear polymer with a molecular weight ranging from 15,000 to
250,000 daltons.4,5 The gelatin polymer chains are composed of
repeating units of about 20 different amino acids with the dicar-
boxylic amino acids (i.e., aspartic acid and glutamic acid) providing
free carboxyl groups, diamine amino acids (i.e., lysine and arginine)
providing free amino groups, and hydroxyl amino acid (i.e., hy-
droxyproline) providing free hydroxyl groups. These functional
groups actively participate in several chemical reactions,6 some of
which will be discussed in later sections. The frequency of occur-
rence of the most abundant amino acids are glycine (~33%), alanine
(~11%), and imino acids (i.e., proline and hydroxyproline; ~22%).7
Gelatin contains all the amino acids commonly found in proteins
with the probable exception of tryptophan and cysteine.

http://dx.doi.org/10.1016/j.xphs.2017.02.006
0022-3549/© 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
1454 R.P. Gullapalli, C.L. Mazzitelli / Journal of Pharmaceutical Sciences 106 (2017) 1453-1465

Capsule Dosage Forms

Soft Shell Hard Shell

Fills Fills
• Non-aqueous solutions, • Powders, pellets, granules
suspensions, semi-solids • Non-aqueous solutions,
suspensions, semi-solids

Gelatin Shell Non-gelatin shell Non-gelatin Shell Gelatin Shell

Gelatin, plasticizer, Starch/Carrageenan, HPMC, Starch, Gelatin, water
water PVA, or Starch/PVA, HPMC/Carrageenan or
plasticizer, water HPMC/Gellan, water

Modified Release (MR) Capsules

• MR coating of filled capsules
• Inclusion of MR polymer in shell before filling
• Filling of MR fill formulation in IR shells

Figure 1. Designs of capsule dosage forms used to encapsulate solids, liquids, and semisolids.

Gelatin is amphoteric in nature with its isoelectric point (i.e., pH
at which the gelatin molecule is electrically neutral) ranging from
7.0 to 9.0 for type A gelatin (i.e., acidic treatment) and from 4.7 to
5.3 for type B gelatin (i.e., alkaline treatment), respectively.5 Type A
gelatin is considered to be less degraded form of collagen relative to
type B gelatin. The acid pretreatment of collagen is thought to
accomplish only a physical reorganization of the collagen structure
with minimal hydrolytic changes. By contrast, the alkali pretreat-
ment of collagen is thought to bring about chemical alterations in
the collagen structure, resulting in the rupture of the relatively
weak physical forces that maintain its fibrillar structure. During
alkali pretreatment, arginine moieties of the collagen can undergo
deguanidination to form ornithine and urea and potentially trace
amounts of citrulline and ammonia (Fig. 2).8-11 The extent of
ammonia evolved increases rapidly upon increasing concentrations
of alkali, but remains low and practically negligible at pH values less
than 5.4 (Fig. 3).12 The presence of even smaller quantities of
ammonia in the gelatin capsule shell may induce degradation of
some encapsulated compounds.13 Collagens from marine sources
are more susceptible to degradation during chemical treatment due
to the lower content of cross-links,14 in contrast to the more stable
collagens from mammals (e.g., collagen from cattle bones, hides,
and pigskins).
Gelatin undergoes hydrolytic degradation in aqueous media, the
rate and extent of which depend up on the pH, temperature, and
time the reaction is allowed to proceed.15-18 The degradation of
gelatin was shown to be minimum between pH values 4 and 7, with
the rate accelerating on either side of this pH region. The hydrolytic
degradation of gelatin results in the reduction of the viscosity and
gel-forming ability (gel strength) of a gelatin solution.
Chemical Structure of Gelatin. Collagen, the parent protein of
gelatin, consists of 3 polypeptide chains, each one twisted in a left-
handed helix and supercoiled together to form a right-handed
triple helix.19,20 In collagen, the single chains (a-chains) cross-link
forming the b-chains (2 covalently cross-linked single chains) and
g-chains (3 covalently cross-linked single chains). The triple helix of
collagen is stabilized by firmly bound water molecules. During the
denaturation process of collagen, the triple helix structure is broken
down to form a random-coil gelatin. In aqueous solutions, the
gelatin chains coil around each other to form a collagen-like triple
helix, when the solution is cooled below its coil to helix (sol to gel)
transition temperature, thereby recreating the 3-dimensional
network.20-22 As the complete reversibility of gelatin transition
into collagen requires the proper juxtaposition and recoiling of the
3 peptide chains and as the chances for such a scenario are less than
possible, it is assumed that gelatin could never be returned to the
complete native collagen structure, but could only be returned to a
partial recovery of the helix structure originally present in the
native collagen.23
High rigidity and elongation at fracture in a gelatin gel is
generally attributed to the helical structure of the macromolecules.
This aspect of gelatin is of critical importance to the formation of
gelatin films and integrity of capsules. When the gel mass is kept at
57 C-60 C, the gelatin in the gel mass exists as single protein
molecules in a random coil configuration, sheathed by water mol-
ecules. As the temperature of the gel decreases below 40 C, the
gelatin molecules begin to re-form into the structural characteris-
tics that are typical to the parent collagen fibers. This conforma-
tional state assumed by gelatin is determined by the molecular
weight, type, and concentration of gelatin in the solution, process
conditions, such as temperature, rate of drying, as well as the na-
ture of the solvent and the content of various salts, denaturating
and structuralizing substances.21-28
The various factors affecting the formation of helical structures
in gelatin solutions can be summarized as below:
1. Related to gelatin:
a. Gelatin requires at a minimum chain length of 40-80 amino
acid residues to form helical structures with their content and
stability increasing with increasing polymer chain length.
Lower temperatures promote the formation of larger helix
contents with longer cooling times providing additional
amounts of helices.21,22,26,29
 R.P. Gullapalli, C.L. Mazzitelli / Journal of Pharmaceutical Sciences 106 (2017) 1453-1465 1455

Figure 2. Possible pathways of deguanidination of arginine moieties in collagen and gelatin.9

b. Type A gelatin, a less modified form of collagen than type B modifications. The chemical modification of the side chains can
gelatin, usually generates more helical structures than type B potentially influence the viscosity and gel-forming properties of
gelatin.21,22,24 gelatin. The carboxylic acid groups produce negative charges on
c. Imino acid (proline and hydroxyproline) content contributes dissociation and can be converted into nonionizable esters by re-
to the mechanism of formation and stabilization of the heli- action with an alcohol in presence of an acid catalyst. The acid
ces in gelatin.21,30,31 Thus, gelatins containing a larger imino catalyst suppresses the ionization of the carboxylic acid groups,
acid content (e.g., gelatins derived from collagen of cattle thereby promoting esterification of those groups.39 The ester con-
bones, hides, and pigskins) usually form stronger gels with tent of gelatin increases with an increase in the concentration of the
superior rheological and thermally stable properties than acid catalyst and the time of reaction. The viscosity of a gelatin
those containing lesser imino acid content, such as fish gel- solution and rigidity of the gel resulting from such a solution
atins.32 Calfskin gelatin, for example, contains approximately decrease with an increase in the ester content of gelatin.6 The esters
138 proline and 94 hydroxyproline residues per 1000 total of gelatin are liable to hydrolysis in the presence of an alkali.
amino acid residues compared to 102 proline and 53 hy- The chemical modification of the free amino groups in gelatin
droxyproline residues in cod (cold water fish) skin gelatin.33 (i.e., lysine) can be achieved by selective treatment of gelatin with
Gelatins from warm water fish species (e.g., tilapia) contain an acid anhydride under alkaline conditions.6,40,41 Under alkaline
approximately 119 and 70 residues of proline and hydroxy- conditions, such as an aqueous sodium acetate solution, the free
proline, respectively, per 1000 total residues, and have amino groups are prevented from ionizing, which promotes se-
physical properties closer to those of mammalian gelatins.34 lective acetylation of only the amino groups.42 Treatment of gelatin
The inferior physical properties and large variations in the with a monocarboxylic acid anhydride, such as acetic anhydride,
quality of different fish gelatins make these gelatins unsuited under alkaline conditions results in the formation of acetylated
as mammalian gelatin replacements. gelatin (a neutral amide) with a reduced isoelectric point.6 The
2. Related to composition of medium: chemical masking of the side-chain free amino groups with a
a. Gelatin generates the highest helical structures when the pH dicarboxylic acid anhydride, such as succinic anhydride, under
of the medium is at the isoelectric point of the gelatin and the alkaline conditions results in the formation of succinylated gelatin
rate of formation of helical structures slows down consider- (an acidic amide due to the presence the second free carboxylic
ably when the pH of the medium moves away from the iso- group), which reduces the isoelectric point of gelatin further,
electric point.21,22,24,26 The influence of the pH of the medium
on the formation of helical structures is diminished as the
temperature is lowered.
b. Nonionic polyhydroxyl solvents and solutes, such as glycerol,
sorbitol, glucose, and sucrose, enhance the formation of he-
lices and the effect increases with increase in their concen-
tration and hydroxyl content (e.g., sorbitol > glycerol, sucrose
> glucose).35,36
c. Citrate solutions may induce reorientation of gelatin mole-
cules into helical structures as suggested by an increase in the
viscosity, with a maximum observable effect at pH near 7.0.37
d. Alcohols inhibit generation of the helical structures with the
longer carbon chain length alcohol imparting greater
inhibition of the formation of helices (e.g., n-propyl alcohol >
ethanol > methanol).24,36
e. Salts, such as sodium chloride and calcium chloride, reduce
the rate of generation of helical structures in gelatin.24
f. Denaturating agents, such as urea, N-methyl acetamide,
thiocyanates, and ionic surfactants, promote the transition of
helical structures into coil structures.25-28,38

Figure 3. Effect of pH of the hydrolyzing solution on the percentage of nitrogen

Chemical Modification of Gelatin. The polar groups present in the evolved as ammonia from collagen. (Reprinted with permission from Bogue.12
side chains of gelatin are reactive and prone to chemical Copyright American Chemical Society)
1456 R.P. Gullapalli, C.L. Mazzitelli / Journal of Pharmaceutical Sciences 106 (2017) 1453-1465
compared to the acetylated gelatin.40 The viscosity of an acetylated
gelatin solution and rigidity of the gel resulting from such a solu-
tion are not influenced by the N-acetyl content of gelatin and are
similar to those of the unacetylated starting material.6 Succinated
gelatin is relatively more permeable to volatile solvents (e.g., ethyl
alcohol) and migratable ingredients than gelatin.
In contrast, the acetylation of the hydroxyl groups in gelatin can
be achieved selectively by treatment either in acetic acid, acetic
anhydride, and perchloric acid medium or in acetic anhydride and
trifluoroacetic acid medium.41 Under acidic conditions, the amino
groups exist in ionized form, which prevents acetylation of those
groups and promotes selective acetylation of the hydroxyl groups
in gelatin. Unlike as in case of amidation of the amino groups with
an acid anhydride, esterification of the hydroxyl groups is known to
have less significant influence on the isoelectric point of gelatin.
The guanidino groups of the arginine residues in gelatin are
responsible for the existence of positive charges on the molecule at
all measurable pH values, because these groups are assumed to
have a pKa value in the region of 14.6 The only reactions specific to
the guanidino groups occur in a strong alkali, which might result in
deguanidination (Fig. 2).
Cross-linking of Gelatin. Gelatin undergoes cross-linking (also
known as pellicle formation) upon aging and when exposed to (a)
physical stress conditions, such as heat,43 high temperature and
humidity,44 UV radiation,45 g-radiation,46-48 and rapid drying,49 (b)
chemical substances, such as aldehydes, ketones, imines, and car-
bodiimides,50-57 or (c) enzymatic substances, such as trans-
glutaminase.54 Aldehydes are thought to form methylene bonds
between 2 amino groups on adjacent gelatin chains or within the
same chain. The aldehyde-induced cross-linking of gelatin is
thought to involve the ε-amino functional groups present in the
lysine moieties and the guanidino functional groups present in the
arginine moieties of the gelatin chain.53,55,56,58 On the other hand,
elevated temperatures are thought to deplete water molecules
between the side-chain carboxylic acid groups on a gelatin chain
and hydroxyl or amino groups on an adjacent gelatin chain
(or within the same chain) and promote formation of esters or
amides, respectively.43
Whether it is thermally induced, chemically induced, or enzy-
matically induced, cross-linking of gelatin results in the formation
of 3-dimensional molecular networks of a higher molecular weight
with the loss of ionizable groups (i.e., R-NH2 and R-COOH) than the
original molecules, leading to the reduced solubility of gelatin. The
loss of ionizable groups in gelatin and the resulting decrease in its
solubility may also arise from the ionic, hydrogen, and van der
Waals interactions of these groups with other compounds used
concurrently in the capsule shell formulations, for example, FD&C
Red # 3 and FD&C Red # 40 colorants.59,60
The cross-linking of gelatin can be reduced by masking the
amino groups available along the molecular chain of gelatin
through covalent bonds with a suitable masking agent, such as
succinic acid.61-63 The dicarboxylic acid nature enables succinic acid
to both the reaction of one carboxylic group with an accessible
amino group in the molecular chain of the gelatin whereas the
second carboxylic group concurrently providing steric prevention
of access of the cross-linking agent. Acetylation of the amino groups
on gelatin is another example that was shown to minimize cross-
linking of gelatin in presence of aldehydes.52
Other solutions to minimize the cross-linking of gelatin include
the following: (a) use of excipients with no or low aldehyde con-
tent, (b) minimize the formation of aldehydes in the excipients by
using appropriate antioxidants, and (c) use of excipients containing
abundant free amino groups (e.g., glycine) in the gel formulation
that can compete with the amino groups present in the gelatin
chain for the available aldehyde impurities. Incorporation of a low-
molecular-weight gelatin hydrolysate containing smaller peptides
of molecular weight of 100 to 1500 daltons, free glycine, and other
amino acids into the gel mass was also reported to reduce the
tendency of gelatin cross-linking.64,65
Microbial Growth in Gelatin. Microbial growth in gelatin may not be
possible due to the lack of the essential amino acid, tryptophan, in
gelatin and the very hypertonic nature (low water activity) of
gelatin, especially in the dried state. Any degree of microbial
growth that could occur in gelatin might probably be due to the
presence of excessive moisture. Microorganisms classified as fungi
(e.g., Aspergillus niger) have the best opportunity of growth in
gelatin when excessive moisture is present. In contrast, bacteria,
yeast, and fungi are not expected to grow in dried gelatin. In the wet
gel masses inoculated with different types of microorganisms, with
the exception of fungi, no other types of microorganisms were re-
ported to survive for longer than 20 days in the gel mass.66 A 5-log
unit reduction in the number of surviving bacteria was observed in
7 days for Pseudomonas aeruginosa, 10 days for Escherichia coli, and
18 days for Staphylococcus aureus, respectively, and in 15 days for
Candida albicans (yeast). In contrast, no observable reduction in the
number of surviving A niger was observed within the study period
of 40 days under similar conditions. The addition of methyl and
propyl parabens, as the preservatives, produce acceleration in the
inactivation of all study microorganisms in the wet gel masses. The
C albicans was shown to be more vulnerable to the parabens than
other bacteria tested. On the other extreme, it required more than
20 days for parabens to produce a 5-log unit reduction in the
number of surviving A niger in wet gel masses.
The reported minimum levels of water activity necessary for the
growth of E coli, P aeruginosa, S aureus, and A niger are 0.93,67
0.94,68 0.86,69 and 0.84,70 respectively. In wet gel masses, water
activity levels were much higher than those required for the sur-
vival of microorganisms. In the case of dried gel masses, the water
activity levels fall to much lower than those required for microor-
ganisms to survive. Thus, gelatin products, when dried properly and
handled with considerable care, provide sufficient microbial
inhibition.66
Plasticizers
Hard gelatin capsule shells do not contain a nonvolatile plasti-
cizer and the presence of moisture (12%-16%) is essential to main-
tain their flexibility and integrity.71,72 At a lower moisture content,
the shells become brittle and are prone to breakage, whereas at a
higher content, the shells may deform and become sticky. Thus, any
alteration to this moisture range, due to its migration between the
shell and encapsulated fill or between the shell and external
environment, could be detrimental to the integrity of the hard
gelatin capsule shells.
A nonvolatile, hydrophilic plasticizer is included in the pro-
duction of gelatin ribbons for soft gelatin capsules. The plasticizer is
hypothesized to reduce the protein-protein interactions with a
consequent increase in the mobility of protein chains and a
decrease in the glass transition temperature (Tg) of gelatin.73 The
reduction in the protein-protein interactions results in improved
flexibility and handling of the shell material during its
manufacturing and shelf life. In addition, a plasticizer, due to its
hygroscopic nature, promotes absorption and retention of moisture
by gelatin that also contributes to the reduction of the forces be-
tween the adjacent polymer chains.73-76
Typical hydrophilic plasticizers used in the soft gelatin capsule
shells include glycerol, sorbitol, partially dehydrated sorbitol (blend
of sorbitol and 1,4-sorbitan), maltitol (hydrogenated corn syrup),
mannitol, propylene glycol, and low-molecular-weight
 R.P. Gullapalli, C.L. Mazzitelli / Journal of Pharmaceutical Sciences 106 (2017) 1453-1465
Figure 4. Influence of (a) glycerol content and (b) RH on oxygen permeability and of
(c) glycerol content on equilibrium water content of gelatin films at 21 C ± 1 C.1,87
(Reprinted with permission from Hom et al.87 Copyright Elsevier)
polyethylene glycols (PEGs). Plasticizers are used typically at about
15%-30% w/w of the total wet mass of a shell formulation at the
time of soft gelatin capsule encapsulation.77-80
1457
Glycerol is the most effective plasticizer, and the higher plasti-
cizing efficacy of glycerol is attributed to its lower molecular weight
and higher hygroscopicity than other higher polyols.73,76,81 The
moisture content of gelatin films plasticized with glycerol tends to
increase with increased glycerol concentration in the films. Sorbitol
is prone to crystallization from gelatin films (blooming) stored at
lower humidity conditions due to the insufficient availability of
water to keep the plasticizer in solution.82,83 As the crystallization
of sorbitol decreases the effective amount of “plasticizing” sorbitol,
it is expected to increase the molecular interactions within the
gelatin network and change the mechanical properties of the
films.82 Glycerol is blended with sorbitol to yield a better control of
the overall moisture content in gelatin films. Alternately, use of
partially dehydrated sorbitol as a plasticizer in gelatin films tends to
pick up less moisture than glycerol and not to prone to crystalli-
zation as regular sorbitol.
Lower-molecular-weight PEGs (e.g., PEG 200 and PEG 300) have
a larger number of hydroxyl groups per mole and a higher hygro-
scopicity compared to those of higher-molecular-weight PEGs and
thus the former exhibit a more pronounced plasticizing effect than
that by the latter. A more efficient plasticizing effect of a lower-
molecular-weight PEG is also due to its smaller molecular size
that facilitates its insertion into the polymer chains of gelatin more
readily. Gelatin films plasticized with PEGs are known to exhibit a
tendency for the plasticizer to migrate to the surface of the films.84
This phenomenon is thought to take place when the plasticizer
concentration exceeds its compatibility limit in the polymer, thus
causing phase separation and physical exclusion of the plasticizer
from the polymer.85 This phenomenon is referred to as blooming or
blushing. The physical exclusion of the plasticizer from the polymer
also results in films becoming opaque with time, with the opacity
increasing with increase in the molecular weight and correspond-
ing increase in the melting point of the PEGs.84
The permeability of oxygen and volatile fill components, such as
ethyl alcohol, through a gelatin film increases exponentially with
an increase in glycerol concentration and corresponding increase in
the humidity in the film (Fig. 4).86-88 The oxygen permeability and
loss of volatile fill components due to diffusion can be minimized
by the use of a non-glycerol plasticizer or substituting a portion of
glycerol with a higher polyol plasticizer, maintaining low shell
moisture content, and protecting the capsule product against high
humidity conditions.
In addition to aforementioned plasticizers of hydrophilic nature,
the use of hydrophobic plasticizers such as oleic acid, triethyl cit-
rate, acetyltriethyl citrate, tributyl citrate, and acetyltributyl citrate
in gelatin films has also been investigated.84,89 Akin to hydrophilic
plasticizers, the hydrophobic plasticizers provide flexibility to
gelatin films. However, the extent of this effect with hydrophobic
plasticizers on gelatin films is far less than that produced with
hydrophilic plasticizers. The hydrophobic plasticizers are also less
compatible with gelatin, resulting in phase separation during the
drying process. Although the addition of an emulsifier such as
lecithin may minimize the phase separation to some extent, films
produced with hydrophobic plasticizers are generally opaque and
the opacity of the gelatin films increases with increased concen-
tration of a hydrophobic plasticizer in the films.
Manufacturing of Capsule Dosage Forms
The manufacturing process for the production of soft gelatin
capsules is the rotary die process,90 in which a molten mass of a
gelatin sheath formulation at 57 C-60 C is fed from a reservoir onto
2 separate rotating cooling drums to form 2 spaced flat ribbons of
gelatin in a semimolten state. These flat ribbons are extracted from
the cooling drums and are fed around rollers that lubricate them,
1458 R.P. Gullapalli, C.L. Mazzitelli / Journal of Pharmaceutical Sciences 106 (2017) 1453-1465
usually with fractionated coconut oil, and then brought together at
a convergent angle into the nip of a pair of roller dies that include
opposing die cavities. A fill formulation, to be encapsulated, flowing
from its own reservoir through a tube under gravity, is fed into a
positive displacement pump. Accurately metered volumes of the fill
formulation are injected from a heated wedge (~35 C-<40 C) into
the space between gelatin ribbons as they pass between the cavities
on the die rolls. As the ribbons meet on the rim of the opposing die
cavities, the bottom lips of the cavities initially seal, forming what is
referred to as “lower seam.” The fill formulation is then injected
precisely into the semi-formed soft gelatin capsules. The soft
gelatin capsule halves are then sealed together (forming the “upper
seam”) by the application of heat (provided by the heated wedge)
and pressure (provided by the dies). The soft gelatin capsules,
severed around each of the die cavities, are ejected by the contin-
uous rotation of the dies and are carried on a conveyer into a
tumble dryer. After the soft gelatin capsules exit the tumble dryer,
they are spread on to shallow trays and dried further in a drying
tunnel maintained at 21 C-24 C and 20%-30% RH.
Empty hard capsule shells of various fill volumes are manufac-
tured separately and supplied ready for the encapsulation of fill
formulations. The manufacturing process for the hard capsule
shells is the dip molding process, in which a set of molding pins are
immersed in an aqueous solution of the film-forming polymer
(gelatin or hypromellose [HPMC, hydroxypropyl methylcellulose])
with other additives, such as a gelling agent and a gelling promoter
(in case of HPMC capsules), an opacifier, and colorants, maintained
at 48 C-55 C. The molding pins with the adhering solution are
withdrawn and dried at 25 C-35 C to form capsule shells (body or
cap). The dried body and cap parts of the capsule shells are cut to a
suitable size and paired to form empty hard capsule shells.
The bodies of hard capsule shells are filled, capped, and sealed
sequentially. Unlike soft capsules, which are 1-piece, completely
filled, and hermetically sealed, filled 2-piece hard capsules have
substantial headspace within. The presence of the headspace
within a hard capsule may compromise the elegance of a product
designed with a transparent shell formulation and the oxidative
stability of an encapsulated compound. The loss of fillable volume
in a hard capsule due to the headspace may also result in a rela-
tively larger capsule size compared to that of a soft capsule
containing a similar fill volume.
An essential part of producing liquid-filled hard capsules is the
ability to seal the capsules effectively after encapsulation. The 2
most widely used methods are banding using a polymer solution
(e.g., gelatin solution for banding hard gelatin capsules) and sealing
using a hydroalcoholic solution.91 The banding of hard capsules is a
process, in which capsules are first rectified and then passed once
or twice over the top of a rotating wheel with its bottom submerged
in a bath of the polymer solution maintained at an optimal viscosity
and temperature. A quantity of the polymer solution is picked up by
the rotating wheel from the bath and applied to the junction of the
cap and body of the capsules. The capsules are then carried through
the drying process.
In the capsule-sealing process, every capsule is individually
sprayed with a micro amount of a hydroalcoholic sealing fluid at
the junction of the cap and body of the capsules followed by drying
by gently tumbling the capsules in a rotating drum. For an efficient
sealing process, it is important that the fill material does not
penetrate into the zone between the body and cap before the
sealing operation.
The challenges arising from the leakage of the hard capsules
may be able to overcome by maintaining the fill formulation in
liquid form during the filling step that solidifies subsequently. This
can be achieved using a thixotropic formulation that remains a
liquid under shear (shear thinning)92,93 or a semisolid formulation
that remains a liquid when heated (hot melt or thermosoften-
ing)93,94 during capsule-filling process. In the case of hot melt fills,
the effect of melting temperature and time held at this temperature
on the potential for the formation of aldehyde impurities and
thermal stability of compounds needs to be investigated. The rate of
cooling can also have an influence on the structure of certain ex-
cipients, which in turn may modify the drug-release characteristics
from the matrix itself.95
The readers are directed to the literature published by
Cole et al.,2 Cade et al.,3 and Rowley96 to obtain any further
understanding of the manufacturing process for the liquid- and
semisolid-filled hard capsules and their characteristics.
Fill Formulations
Until early 1980s, soft gelatin capsules were traditionally used to
encapsulate nonaqueous liquid and semisolid formulations,
whereas hard gelatin capsules were used to encapsulate powders
and pellets. Later on, hard capsules were evolved as an alternate to
soft gelatin capsules for encapsulating nonaqueous liquids and
semisolids.2,3,93,97 The hard capsule shells for liquid and semisolid
filling are identical in composition to those used for filling powders
and pellets.
Lipophilic vehicles, such as long-chain free fatty acids and their
esters, are compatible with both soft and hard capsules. Hydro-
philic vehicles for soft gelatin capsule fill formulations include PEGs
of 400-600 molecular weight and smaller amounts of propylene
glycol, glycerol, and water. The use of propylene glycol, glycerol,
water, and lower-molecular-weight PEGs (molecular weight  300)
in the fill formulations is limited due to their ability to diffuse into
the shell and thereby act as gelatin plasticizers.84,98 Hydrophilic fill
formulations have an affinity for water and glycerol used in
the shell formulation as plasticizers, leading to the migration of
these shell components into the fill. Migration of a plasticizer from
the shell into the fill in a soft gelatin capsule could result in the
reduced elasticity and increased brittleness of the shell shortly after
production or on storage, especially when exposed to cold tem-
peratures.78,99,100 Migration of water could lead to physical and
chemical instability of soft gelatin capsule products containing
solubilized compounds, which are prone to water-induced pre-
cipitation and hydrolytic degradation.101-105 PEG and lipid excipi-
ents are inherently susceptible to autooxidation in the presence of
air, moisture, heat, and light and produce reactive peroxides, al-
dehydes (i.e., formaldehyde and acetaldehyde), and carboxylic
acids (i.e., formic acid and acetic acid). These reactive impurities are
known to induce physical and chemical instability in capsule
products.106-113
Hard gelatin capsule shells are compatible with PEGs of mo-
lecular weight higher than 4000.2,97 PEGs of molecular weight 
4000, due to their hydrophilicity, can extract water from the shell
material, resulting in increased brittleness of the shell shortly after
production or on storage. Use of water, glycerol, sorbitol, and pro-
pylene glycol in the fill formulations is known to be incompatible
with the hard gelatin capsule shells at concentrations as low as 5%.3
It is essential to keep the apparent pH of the fill formulation
between 2.5 and 7.5 to maintain the structural integrity of gelatin
capsule shell during its shelf life. At pH values outside this range,
gelatin is hydrolyzed causing leakage of capsule fill contents and
sticking of the capsules.16,114 Gelatin shells containing encapsulated
acid salts, mineral acids, and organic acids may also be at the po-
tential risk of hydrolysis of gelatin due to the migration of these
compounds into the shell.115,116
The use of ethyl alcohol, a commonly used cosolvent in self-
emulsifying fill formulations, is limited due to its ability to
rapidly diffuse through the capsule shell.86,88,117 The loss of ethyl
 R.P. Gullapalli, C.L. Mazzitelli / Journal of Pharmaceutical Sciences 106 (2017) 1453-1465
alcohol from a self-emulsifying fill formulation could have a sig-
nificant negative impact on the solubility of a dissolved compound
and in vitro and in vivo performance of the formulation.118-120
Non-Gelatin Capsule Dosage Forms
Non-Gelatin Hard Shell Capsules
HPMC-Based Hard Shell Capsules
Alternate to hard gelatin capsules, hard capsule shells are also
manufactured using non-gelatinous polymers, such as HPMC and
starch. The originally invented HPMC capsule shells contain a sec-
ondary gelling agent such as kappa-carrageenan (Quali-V® from
Qualicaps) or gellan (Vcaps® from Capsugel). HPMC alone does not
gel at low temperatures. The use of a gelling agent is essential to be
able to manufacture HPMC capsule shells using the conventional
dip molding process employed in the manufacture of hard gelatin
capsule shells. Carrageenans are algal (seaweed) polysaccharides
consisting of high-molecular-weight linear sulfated galactan
chains. Gellan gum is a microbial polysaccharide with a linear
tetrasaccharide-repeating sequence with 1 carboxyl group per
repeat unit. In solution, at the dipping stage of capsule shell
manufacturing, both gelling agents exist as disordered coils.121 On
cooling, the chains associate by the formation of double helices.
Gelation occurs by subsequent aggregation of these helices to form
a continuous, 3-dimensional network. Gelation is further promoted
by cations that suppress the electrostatic repulsion between the
helices and allow aggregation to occur. Divalent metal ions, such as
calcium, are particularly effective in inducing gelation of gellan and
carrageenan.122,123 Monovalent cations, such as potassium, also
produce strong gels at moderate salt concentrations.123,124 Newer
version of HPMC capsule shells without a secondary gelling agent
and a gelling promotor have also been manufactured and are
available under the trade name Vcaps® Plus (Capsugel).
The use of a gelling agent is known to delay the HPMC shell
dissolution in vitro and in vivo in some circumstances.121,125 The
dissolution of the HPMC capsule shells containing a gelling agent is
dependent on both pH and composition of the dissolution medium
and is usually longer than that of hard gelatin capsules. The delay in
the dissolution of these HPMC capsule shells is attributed to the
interactions between the gelling agent and cations such as potas-
sium and calcium present in the dissolution medium. The newer
HPMC capsule shells (Vcaps® Plus) without a secondary gelling
agent exhibit dissolution independent of both pH and ionic nature
of the dissolution medium.126-129
Cole et al.121 discussed the influence of pH and composition
of the dissolution medium on the dissolution of the HPMC
capsule shells containing a gelling agent in some detail. If water
is used as the dissolution medium, both gellan and carrageenan
gels dissociate because of diffusion of cations out of the gel
network, resulting in rapid film disruption of capsule shells and
fast drug release.124,129,130 However, in acid conditions, the 2
gelling agents behave differently. Carrageenan at pH 1.2 behaves
in the same way as in water, because the sulfate groups, having
very low pKa, retain their negative charge, which disrupts helix-
helix aggregates by electrostatic repulsion when the gel-forming
cations diffuse into the surrounding acidic solution. The carboxyl
groups of gellan gum, on the other hand, have a much higher
pKa (~3.4), and therefore convert into the uncharged (-COOH)
form at low pH, with consequent elimination of electrostatic
repulsion between the helices.123 Gellan gels, therefore, are less
soluble at pH 1.2.
When the dissolution medium contains sufficient gel-forming
potassium cations, dissociation of the helix-helix aggregates is
hindered with the result that the gel from gellan and carrageenan
1459
retains its structure and the solubility is reduced. When the
dissolution medium contains sodium cations, disruption of the film
is faster than if potassium cations are present. The reason for this
difference is thought to be due to the binding efficiency with which
ions of different sizes can fit into potential sites on the helices.
Dissolution behavior of HPMC capsule shells containing the gelling
agents in TRIS buffer, which contains no metal cations, is similar to
that in water.
HPMC capsule shells have 3-fold lower average moisture
content (2%-6%) and are less hygroscopic than hard gelatin
capsule shells.126,131 The presence of 12% to 16% water in the hard
gelatin capsule shells, as a plasticizer, is essential to maintain
their integrity and flexibility.71,72 Any alteration to this moisture
range could be detrimental to the integrity of the hard gelatin
capsule shells. As HPMC capsule shells are less dependent on
water as a plasticizer, these shells are less likely to break even in
dry conditions, thus helping to maintain physical stability of
products against breakage.132 As a consequence of being less
hygroscopic and having a lower moisture content, moisture
transfer from the HPMC capsule shells into the encapsulated fill
material could potentially be reduced, thus maintaining physical
and chemical stability of products containing compounds prone
to water-induced precipitation and hydrolysis. An additional
advantage of HPMC capsules is any polar and hygroscopic sol-
vents present in the fill formulations are less likely to migrate into
the capsule shell or to interact with the shell material. Unlike
gelatin, HPMC is a nonionic polymer and has less compatibility
challenges with most encapsulated materials and aldehyde
impurities present therein.131
Scanning electron microscopy studies suggest that HPMC films
may have looser structure compared to gelatin films, resulting in
their relatively higher oxygen permeability. However, water vapor
permeability through gelatin films is relatively higher than through
HPMC films. Higher oxygen permeability through HPMC films is
attributed to the looseness in the structure of these films, whereas
higher water permeability of gelatin films is attributed to the hy-
groscopicity of these films.131 When oxygen-sensitive compounds
are encapsulated into HPMC capsules, it is recommended to include
an antioxidant in the fill formulation or to package the capsule
product into an oxygen-resistant configuration such as blister
package with aluminum foil.132
In vivo gamma scintigraphic studies in human subjects by Tuleu
et al.133 and Jones et al.134 comparing HPMC capsules containing
kappa-carrageenan as a gelling agent with hard gelatin capsules
suggested no significant differences in the disintegration times in
either fasting or fed state (mean ± SD): 8 ± 2 min and 7 ± 3 min for
HPMC and gelatin capsules, respectively, under fasting condition
and 16 ± 5 min and 12 ± 4 min for HPMC and gelatin capsules,
respectively, under fed condition. In contrast, in vivo disintegration
studies by Cole et al.121 using gamma scintigraphic technique
demonstrated delayed capsule disintegration (both initial and
complete) for HPMC capsules containing gellan as a gelling agent
compared to that of gelatin capsules, for example, initial disinte-
gration at 0.47 ± 0.17 h versus 0.13 ± 0.06 h and complete disin-
tegration at 0.69 ± 0.29 h versus 0.24 ± 0.14 h for HPMC and gelatin
capsules, respectively, under fasting condition. Whereas under fed
condition, the initial disintegration times were 1.00 ± 0.37 h and
0.39 ± 0.36 h and the complete disintegration times were 1.61 ±
0.65 h and 1.22 ± 0.80 h for HPMC and gelatin capsules, respec-
tively. However, these differences in the disintegration times
between HPMC and gelatin capsules were found to have no sig-
nificant effect on the AUC(0 ∞) and Cmax of the encapsulated com-
pound in the study subjects. Orally administered formulations in
HPMC and gelatin hard capsules were also shown to be inter-
changeable by several other investigators.131,135
1460 R.P. Gullapalli, C.L. Mazzitelli / Journal of Pharmaceutical Sciences 106 (2017) 1453-1465
Figure 5. (a) Starch hard capsules produced by injection molding process and (b) cap and body design differences between starch and gelatin hard capsules. (Figure 5a is reprinted
with permission from Vilivalam et al.137 Copyright Elsevier Science and Figure 5b is adopted from Eith et al.136)
Starch-Based Hard Shell Capsules
Hard capsule shells using potato starch as the film-forming
material have been manufactured using the injection molding
process and are available under the trade name Capill®.136-138 These
capsule shells are made of 2 pieces, a cap and a body, which can be
sealed together at the time of filling to prevent their separation.
Sealing is achieved by applying a hydroalcoholic solution to the
inner section of the cap, immediately before it is being placed onto
the body. The moisture content of starch capsule shells ranges
between 12% and 14% w/w, with more than one-half of it being
tightly bound to the starch. The dissolution of starch capsule shells
is independent of pH. Studies, using amoxicillin as a model drug,
demonstrated that the GIT transit times and plasma amoxicillin
concentrations were similar between the starch and gelatin cap-
sules in normal human volunteers under fasting condition.139
The caps and bodies of the Capill® starch capsules are manu-
factured separately in different sizes (sizes 0, 1, 2, 3, and 4). The
same-sized cap is designed to fit different body lengths as the
diameter of the junction of the cap and body is always the same for
all sizes of starch capsules. Unlike the “lipped” seal on hard gelatin
and HPMC capsules, the starch capsule cap fits evenly in place over
the body, leading to a smooth surface finish. The area of closure
between the cap and body of starch capsules is much smaller
compared to that of hard gelatin capsules. It is because the di-
mensions are more tightly controlled in injection molding process
used for the production of starch capsules than in dip molding
process used for the hard gelatin capsules (Fig. 5).136-138 The su-
perior film adhesion properties of starch capsules compared to hard
gelatin capsules make them amenable to coating process in the
preparation of modified-release dosage forms.94 Coating of starch
capsules can also be considerably easier due to their smooth seal,
coupled with their higher bulk density. However, the starch hard
capsules have not gained wide acceptance due to the need for
different design capsule-filling equipment.
Non-Gelatin Soft Shell Capsules
The necessary properties required of polymer films for the
manufacture of soft capsules using the rotary die process include
(a) the ability of the film-forming composition to be cast to form a
continuous film that is mechanically strong and exhibits elasticity
sufficient to allow the film to stretch during filling and (b) the
ability of the film forming the 2 halves of the soft capsule to fuse
together during the sealing process under sufficient pressure and
temperature.140,141 The temperature at which the fusion of the 2
opposing films occurs during encapsulation should be below the
melting point of the film. This property of fusion temperature being
lower than melting temperature is crucial to the manufacturing of
capsules using the continuous rotary die process. If the fusion and
melting temperatures are about the same, the film will nearly
completely melt during sealing of capsules. It has proven difficult to
find this combination of properties in non-gelatin polymer systems,
which are typical to the gelatin polymer.
Starch and its derivatives in combination with other polymers
have been investigated as gelatin substitutes in the production of
soft capsules.140-142 Tanner et al.140,141 patented compositions
comprising a modified starch with a hydration temperature of less
than 90 C, iota-carrageenan, an optional plasticizer, and sodium
phosphate dibasic buffer for use in the manufacturing soft capsules.
In the conventional rotary die process used to manufacture soft
gelatin capsules, a spreader box metering device is typically
employed to cast films of a gelatin shell composition onto a chilled
surface of the casting drum. As the viscosities of non-gelatin shell
compositions are much higher (10,000 to above 30,000 cps.)
compared to those of gelatin shell compositions, it is difficult to use
the conventional spreader box metering device in the
manufacturing of non-gelatin soft capsules. Thus, melt-extrusion
devices are employed as alternative to the spreader boxes.143 The
non-gelatin polymer blends are melt extruded to produce films that
are fed directly onto the surface of the casting drum to produce soft
capsules. In contrast to soft gelatin capsules which require the
apparent pH of fill formulations be controlled between 2.5 and 7.5
to maintain their stability,16 the starch-carrageenanebased soft
capsules were found to display high resistance to concentrated fills,
alkaline fills, and those containing salts of weak acids and strong
bases.144
Brown144 proposed using polyvinyl alcohol (PVA) films for the
encapsulation process. Such films are available commercially
 R.P. Gullapalli, C.L. Mazzitelli / Journal of Pharmaceutical Sciences 106 (2017) 1453-1465
(Hi-Selon™, Nippon Gohsei) or may be melt extruded at the time of
encapsulation process. These films are partially hydrated just
before encapsulation to improve their flexibility, adhesivity, and
ability to glue the 2 halves of soft capsules within the die cavity
during encapsulation process. Misic et al.145 introduced starch-
PVAebased soft capsules comprising a blend of starch, PVA, and
plasticizers (sorbitol solution and glycerol), produced by extrusion
and subsequent rotary die encapsulation processes. These films
were produced by initially extruding a mixture of potato starch and
PVA with plasticizers through a double-screw extruder to form
granules. These granules were again extruded using a single-screw
extruder and the extrudate was pressed through a slit die to form a
film for encapsulation. In contrast to soft gelatin capsules where
considerable water migration from the soft gelatin shell into a
hydrophilic fill formulation and resulting drug crystallization may
potentially occur, the risk of any substantial water migration or
drug crystallization in starch-PVAebased soft capsules was found
to be minimal or absent.145 The starch-PVA-based soft capsules
were also found to exhibit more surface roughness and higher
resistance to mechanical deformation compared with soft gelatin
capsules. The surface roughness and higher mechanical strength of
the starch-PVAebased soft capsules would make these capsules
more amenable to successful coating process.
Modified-Release Capsule Dosage Forms
Coating of a solid dosage form such as tablets and pellets is
routinely applied to protect the dosage form and its contents
against moisture and oxygen, to mask unpleasant taste and odor, to
improve elegance, and to control the site or rate of release of a drug.
Enteric coating is desirable for the administration of medications,
which cause gastric distress or are unstable in the stomach acid
environment. In addition to enteric coating, which delays the
release of a drug from the dosage form until it reaches small in-
testine, other types of coatings are also applied to deliver a drug at
an intended site of the GIT (site-specific release) or to release a drug
over an extended period (extended release).
The enteric coating materials are carboxylic group containing
polymers, such as cellulose acetate phthalate, hydroxypropyl
methylcellulose phthalate, hydroxypropyl methylcellulose acetate
succinate, polyvinyl acetate phthalate, acrylic acid copolymers, and
shellac. These enteric polymer compositions can be applied onto
dosage forms as aqueous dispersions or organic solutions. Coating
of tablets and pellets can be achieved relatively easily by known
coating processes (e.g., pan coating or fluidized bed coating) owing
to their porous surfaces, which readily adhere to the coating sub-
stances. In contrast, difficulties arise when coating gelatin capsules
because of their smooth, nonadsorptive surfaces and flexibility. The
gelatin capsule shells may soften and become sticky during the
coating process due to solubilization of gelatin.146 In addition, the
gelatin shells may become brittle during the drying process and
prone to breakage under only slight pressure. The acidic enteric
polymers are also thought to possibly penetrate the gelatin shells
and cause the embrittlement therein.
The surface of the gelatin capsules with an improved capacity for
adhering to coating compositions may be achieved by applying to the
outer surface of the capsules a layer of a subcoating of HPMC,146,147
hydroxypropyl cellulose,148,149 polyvinylpyrrolidone,148 or cationic
methacrylate/neutral methacrylate polymers.150,151 This subcoating
is thought to provide the gelatin capsules with better mechanical
strength and improved capacity for adhering to the coating com-
positions. The subcoating layer can also prevent the penetration of
the highly acidic enteric polymers into the gelatin shells and thereby
prevent their embrittlement.151 The addition of PEG 400 and PEG
6000 to the coating formulation was also reported to provide
1461
improved adhesion of the polymer to the gelatin shell.146 Scanning
electron microscopy studies suggest that, in contrast to gelatin
capsules, HPMC capsules have rough surfaces, which provide for
good adhesion to the coating.148,152
Studies by Dvor
ackova
et al.148 suggest that hard gelatin cap-
sules can be coated directly with organic enteric polymer solutions
at lower coating levels without any challenges. These lower coating
levels may not be sufficient to cover the junction zone between the
capsule body and cap and to provide sufficient enteric protection to
the capsules.148,149 However, these gelatin capsules were shown to
display “orange peel effect” at higher coating levels, which was
eliminated by subcoating the capsules with a hydroxypropyl cel-
lulose (HPC) intermediate layer.148 The HPMC capsules, on the other
hand, were successfully coated at all coating levels with organic
enteric polymer solutions without an HPC intermediate layer. It
appears that the application of an HPC intermediate layer is
necessary for practical utilization of enteric coatings onto gelatin
capsules. Dvora
ckova
et al.148 speculated that the intermediate
subcoat changed the smooth surface of gelatin capsules that made
these capsules amenable to enteric coating.
The enteric-coated capsules may also require an overcoat typi-
cally composed of HPC or HPMC to improve the physical stability by
preventing adhesion of capsules together and chemical stability on
storage and during stability studies, especially under accelerated
stability conditions (40 C/75% RH).146,149 The enteric polymers are
known to undergo hydrolysis, thereby reducing their enteric
effectiveness with time.149 The overcoat can minimize the moisture
transfer through the film and thereby reduce the hydrolysis of the
enteric polymer and improve the stability of the coated capsules.
Alternate to the surface coating of capsules with enteric poly-
mers, enteric capsules can also be manufactured by incorporating
the enteric polymers within the capsule shell itself.153-156 These
enteric capsules were shown to be soluble in or disintegrated by the
intestinal secretions but insoluble or resistant to the acid secretions
of the stomach. As an approach, patented by Okajima,153 the body
and cap portions of hard shell capsules can be formed by dip
molding using a homogeneous film-forming mixture comprising a
film former such as HPMC or gelatin, an ammonium salt of cellulose
acetate phthalate polymer or of a copolymer of methacrylic acid
and methacrylic acid alkyl ester, and with an optional plasticizer.
The body and cap portions of such acid-resistant 2-piece hard
capsules can be sealed with an acid-resistant banding solution to
achieve increased acid resistance.157,158
Ready-to-use enteric hard capsule shells in which the enteric
polymer is already incorporated within are commercially available
(DRcaps™, Vcaps™ Enteric, and enTRinsic™ from Capsugel), which
can be filled with formulations.156 Capsugel Vcaps® HPMC hard
capsule shells contain a small amount of gellan as the gelling agent
(typically below 1 part by weight per about 100 parts by weight of
HPMC) and either ethylenediamine tetra acetic acid or sodium citrate
as a gelling promoter.126 The use of a gelling agent is essential to be
able to manufacture HPMC hard capsule shells using the conven-
tional dip molding process. The carboxyl groups of gellan have a pKa
around 3.4 and convert into the unionized form (-COOH) with a
lower aqueous solubility at pH 1.2, thus providing some level of
enteric protection. The lower amounts of gellan used in the Vcaps®
HPMC capsules, however, do not provide sufficient acid resistance to
qualify for the enteric dosage form (i.e., to meet compendial disso-
lution test requirements for enteric products). Use of higher amounts
of gellan may cause excessive increase in viscosity of the aqueous
composition, thus making it difficult to manufacture the capsule
shells at the commercially desirable high speeds and quality using
the conventional dip molding process. Cade and He156 identified that
when the hard capsule shells (DRcaps™ from Capsugel) were pro-
duced at 4 to 15 parts by weight of gellan per 100 parts by weight of
1462 R.P. Gullapalli, C.L. Mazzitelli / Journal of Pharmaceutical Sciences 106 (2017) 1453-1465
HPMC, such capsule shells can exhibit acid resistance for at least 1 h
at pH 1.2 and also can be produced without compromising pro-
cessability during the conventional dip molding process. These
compositions also provide an advantage of not requiring any addi-
tional gelling promoter. Ready-to-use Capsugel Vcaps® Enteric HPMC
capsule shells contain hydroxypropyl methylcellulose acetate succi-
nate to provide enteric protection.
In another approach, Hassan et al.154 and Rao and Khadgapa-
155
thi presented compositions comprising of gelatin, an enteric
polymer, an aqueous alkaline solvent, and a plasticizer to manu-
facture enteric soft gelatin capsules using rotary die process. This
approach provides a method for manufacturing enteric soft cap-
sules without the need for coating. In this approach, the enteric gel
mass is prepared by initially dissolving the enteric polymer in an
aqueous solution of an alkali to get a clear enteric polymer solution.
Gelatin is wetted with water and a plasticizer separately in a heated
vessel, which is then mixed with the enteric polymer solution to
make a final clear homogeneous gel mass. The gel mass is degassed
under vacuum to remove any entrapped air and excess of the alkali.
The step to neutralize (ionize) the enteric polymer with an alkali
before addition to the gel mass is essential in producing clear gel
films for encapsulation. Gel films produced without the neutrali-
zation step are usually cloudy. A volatile alkali such as ammonium
hydroxide is preferred as it is easier to remove any excess amount
during degassing the gel mass. Neutralization of the enteric poly-
mer can also be achieved using a basic amino acid such as argi-
nine.159 However, gel films produced using the basic amino acids
are usually cloudy due to the weak neutralizing capacity of these
basic amino acids. The cloudy appearance these enteric gelatin
films can be improved by the use of increased amounts of a hy-
drophilic plasticizer.
Valproic acid delayed-release soft gelatin capsules (Stavzor®;
Banner Pharmacaps, Inc.) were commercially available in 125 mg,
250 mg, and 500 mg strengths for the treatment of seizure disor-
ders, manic episodes, and migraine prophylaxis. The immediate-
release valproic acid dosage forms are associated with gastric side
effects such as nausea and vomiting. The delayed-release property
is purported to help alleviate these side effects. The Stavzor®
delayed-release soft gelatin capsules contain neat valproic acid fill
encapsulated in a soft shell comprised of gelatin, methacrylic acid
copolymer, glycerin, triethyl citrate, ammonium hydroxide, and
water (NDA 22-152; FDA approval package160).
The choice of the salt form used to prepare the enteric coating
solution can influence the disintegration properties of the enteric-
coated capsules. Al-Gousous et al.161 demonstrated that the shellac-
based enteric coatings obtained using alkali metal salts (sodium
and potassium) display faster disintegration properties of capsule
shells compared to those obtained using ammonium salts. The
films cast from ammonium-based salts of shellac, unlike those cast
from alkali metalebased salts, were also shown to be water insol-
uble. Al-Gousous et al.161 hypothesized that the loss of ammonium
as ammonia and resulting reduced degree of shellac ionization
during drying was a probable explanation for the loss of disinte-
gration properties of the enteric-coated capsules with ammonium
salts compared to those with alkali metal salts.
Before the application of polymers to effect enteric properties to
gelatin capsules, gelatin capsules were rendered resistant to gastric
juices by treating them with formaldehyde either in gaseous state
or in solution state.162,163 However, it is very difficult to control the
exposure of the gelatin capsules to formaldehyde to yield consis-
tent gastric juiceeresistant and intestinal solubility properties of
the capsules. In addition, these properties of formaldehyde-treated
gelatin capsules tend to change with time.149 The stomach and
intestinal solubilities of the gelatin capsules treated with formal-
dehyde also depend on the levels of digestive enzymes (e.g., pepsin
and pancreatin), which are known to show significant inter- and
intrasubject variability. In contrast, the dissolution of capsule shells
containing enteric polymers is exclusively dependent on the pH of
the digestive juices and not on the levels of digestive enzymes.
Selection: Soft Capsules Versus Hard Capsules
When a compound is formulated in a nonaqueous vehicle, the
choice to encapsulate the formulation into soft capsules or hard
capsules is determined by several factors.
a. Tolerance of the capsule shell toward the fill composition:
Any alteration to the moisture range outside 12%-16% in the hard
gelatin capsule shells due to its migration could be detrimental to
the integrity of the shells. Hard gelatin capsule shells filled with
PEG 400 and PEG 600 are prone to become fragile and breakage due
to the migration of moisture from the capsule shell into the PEG fill.
These lower-molecular-weight PEGs are also expected to migrate
into the hard gelatin capsule shells and soften them due to their
plasticizing effect. Hard gelatin shells, on the other hand, have been
reported to be compatible with PEGs of molecular weights higher
than 4000. In contrast, the presence of a plasticizer in the soft
gelatin capsule shells imparts elasticity that allows the shells to
accommodate a wide range of hydrophilic excipients such as PEG
400 and PEG 600. Lipophilic vehicles are compatible with both soft
and hard capsule shells.
b. Tolerance of the fill formulation toward the shell water content:
Soft gelatin capsule shells typically contain water from 30% to
40% w/w at the time of encapsulation process and about 8% to 10%
during the shelf life.164 Depending on the nature of the fill formu-
lation, it may pick up and retain water anywhere from near 0%
(e.g., soybean oil, olive oil) to 10% (e.g., PEG 400).164 In contrast,
though, hard gelatin capsule shells may contain water from 12% to
16%,71,72 the absolute water amount is relatively much lower
compared to soft gelatin capsule shells (as hard capsule shells are
much thinner and lighter) and also is in the bound state, the extent
of its migration into the fill and thus any adverse influence on the
crystallization and to hydrolytic degradation of encapsulated
compounds is minimal. As HPMC hard capsule shells contain even
much lower water content (2%-6%)126,131 compared to those of hard
gelatin capsules, the extent of water migration and its adverse in-
fluence on the stability of encapsulated compounds are even much
lower in HPMC capsules. Thus, the relative stability against crys-
tallization and/or to hydrolytic degradation of encapsulated com-
pounds in capsules follows the order: HPMC capsules > hard gelatin
capsules > soft gelatin capsules.
Aspirin is proven to be difficult to formulate in vehicles for
encapsulation into capsules due to its potential hydrolysis to sali-
cylic acid. United States Pharmacopeia and National Formulary
limits the presence of salicylic acid content in aspirin dosage
forms at not more than 3%. Aspirin is stabilized in the capsule
product by formulating as a lipid suspension and encapsulating into
HPMC hard capsules (NDA 203697; PLx Pharma Inc.).165
c. Physical characteristics of fill formulation:
When a compound is formulated as a low-viscous, nonaqueous
solution, soft capsules may be ideal to deliver the solution. As soft
capsules are filled entirely with no headspace and sealed hermet-
ically, the likelihood of leakage of low-viscous fill materials is
reduced and oxidative stability of encapsulated compounds is
improved. In contrast, the presence of headspace and moderately
 R.P. Gullapalli, C.L. Mazzitelli / Journal of Pharmaceutical Sciences 106 (2017) 1453-1465
sealed junction in hard capsules may compromise oxidative sta-
bility of encapsulated compounds and may risk leakage of low-
viscous fill materials.
Fill formulations requiring encapsulation at temperatures much
higher (e.g., hot melts, high-viscosity fills) than what soft gelatin
capsule encapsulation process can tolerate (~35 C-<40 C) can be
readily encapsulated into hard capsules. The commercially avail-
able vancomycin capsules are produced by filling a dispersion of
vancomycin hydrochloride in PEG 6000 into hard gelatin capsules
at temperatures higher than the melting point of PEG 6000
(55 C-63 C).166 Vancomycin hydrochloride is highly hygroscopic
and picks up moisture rapidly and extensively during routine
pharmaceutical processing operations and on storage. PEGs with
molecular weights 4000 and higher exhibit minimal moisture up-
take when exposed to elevated RH conditions.167 In vancomycin
capsule product, PEG 6000 provides protection to vancomycin
against high RH conditions and thus improves the stability of
vancomycin.166 Fill formulations requiring higher encapsulation
temperatures, such as higher melting point PEGs and waxes can
generate aldehydes that may potentially cross-link gelatin and
reduce the dissolution of gelatin capsule shells. Use of HPMC
capsule shells may be sensible in those cases.
d. In-house existing development and manufacturing capabilities:
Manufacture of soft capsules is inherently a very complex, labor-
intensive, cost-intensive, and time-consuming process that re-
quires not only acquiring and maintaining specialized and costly
equipment but also developing in-house technical and operational
expertise. As a result, organizations are reluctant to set up their
own soft capsule manufacturing operation in-house and prefer to
outsource these activities to an external contract manufacturer. As
empty hard capsule shells of desired features (i.e., size, color, and
logo) and equipment for filling and sealing the capsule shells are
readily available, it is easier for an organization to set up capabilities
and manufacture hard capsule products in-house.
Conclusion
Polymeric film-forming materials and manufacturing technol-
ogies used in the production of capsule shells have been developed
to offer additional consumer acceptability, to improve the dosage
form physical and chemical stability, and to modify release of the
encapsulated contents from the dosage form. These developments
resulted in the use of HPMC and starch-based polymeric materials
as alternate to the animal source gelatin in the manufacture of
capsule shells. HPMC capsule shells have lower moisture content
and hygroscopicity than gelatin capsule shells. As a result, moisture
transfer from the HPMC capsule shells into the encapsulated fill
material is lower and thus the physical and chemical stability of
HPMC shellebased products containing compounds prone to
water-induced precipitation and hydrolysis is improved. Gelatin
and non-gelatin capsule shells can also be formulated to modify the
release of their fill contents in a site-specific manner in the GIT
either by coating the filled capsules with a modified-release poly-
mer or by incorporating the polymer within the capsule shell
before filling. These modified-release capsule shells are soluble in
or disintegrated by the intestinal secretions but resistant to the acid
secretions of the stomach.
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